This invention generally relates to methods for making fine particles, especially particles formed of proteins and peptides.
Fine uniform particles, or powders, are useful in a variety of applications, including medical and pharmaceutical applications such as drug delivery and diagnostics. One example is in aerosol delivery systems to deliver drugs to the lung. The size of the particles delivered directly affects whether the drugs are delivered to the lungs as desired. Accordingly, processing methods which result in fine powders of uniform particles are highly desirable for pulmonary drug delivery, as well as other applications.
Current material processing techniques for making fine, uniform particles in these size ranges include micromilling and precipitation from a solvent. Micromilling, however, can produce locally extreme conditions (e.g., high temperatures) which are capable of altering proteins and peptides. These alterations are unacceptable for fragile materials, especially those intended for administration in pharmaceutical applications. Therefore, precipitation from solvents has been widely used to produce fine powders from fragile materials. Examples of precipitation from solvent methods include anti-solvent systems and super saturation produced by externally changed solubility.
The effectiveness of conventional precipitation from solvent methods, however, generally is limited by the mobility of the precipitate, which allows for assembly of amorphous “clusters” of variable size or microcrystalline particles. The mass of the resultant particle is controlled primarily by the mobility of the precipitant during the interval between supersaturation and exhaustion due to deposition on growing nucleation sites. For example, if the precipitant has a low mobility, the particles formed will have a low mass, while greater mobility generally increases the mass of the resulting particle. Simply diluting the solution is insufficient, since dilute solutions generally do not result in a precipitate. Therefore, in order to obtain fine particles using precipitation from solvent methods, it would be desirable to be able to control, i.e. restrict, the mobility of the precipitant while solvent removal is undertaken.
It is therefore an object of this invention to provide methods of forming fine, uniform particles from fragile materials.
It is another object of this invention to provide methods of forming fine particles using solvent removal methods having reduced precipitant mobility.